The objective of this research is to develop and translate into early phase clinical trials novel immunotherapeutics for the treatment of Acute Myelogenous Leukemia (AML). Less than half of AML patients are cured with current treatment approaches, and relapse and refractory AML patients who are not candidates for hematopoietic stem cell transplantation (HSCT) have no curative treatment options. The role of the immune system in the control and eradication of leukemia is evident in the reduced relapse rate after allogeneic HSCT compared with syngeneic or autologous transplantation. Since allogeneic HSCT is associated with significant morbidity and mortality, it is important to develop alternative immunotherapies for AML. We will investigate novel immunotherapeutic approaches for AML in the following specific aims: Aim 1: To conduct a first-in-human Phase I clinical trial of MGD006, a CD123CD3 Dual Affinity Re-Targeting (DART) bi-specific antibody-based molecule, in patients with high risk AML. This study is designed in three segments: a Single Patient Dose Escalation segment, followed by a Multi-Patient Dose Escalation segment and finally a Maximum Tolerated Dose and Schedule expansion segment. Aim 2: We will characterize the immunomodulatory activity and potential anti- tumor activity of MGD006 in patients with AML. Correlative study samples obtained in Aim 1 will be analyzed for (i.) serum cytokines, (ii.) AML and T cell subset numbers, phenotype and function and (iii.) the sub clonal architecture of AML blasts and T cells. Aim 3: We will identify novel targets for immunotherapy in human AML and test the efficacy of new retargeting agents to kill AML blasts expressing CD123 or these novel targets. We will use banked AML and normal CD34+ stem cells to identify differentially expressed surface proteins in AML. We will also examine alternative retargeting agents (CD123xCD16, CD123xCD47, and CD123xCD3xPD1) and effector cells (resting and CIML-NK cells) for their efficacy in killing leukemic blasts. If our phase 1 clinical trial with MGD006 shows a good safety profile with clear and meaningful signs of efficacy in patients deemed to have a poor prognosis, we will pursue further investigation of the approach in a phase 2 trial. Our studies in Aim 3 will attempt to identify novel antigens on AML cells and develop alternative retargeting agents that engage either T cells, NK cells or other immune effector cells.